Cytoreductive Surgery plus Hyperthermic Intraperitoneal Chemotherapy on Gastric Cancer Peritoneal Carcinomatosis: A Systemic Analysis
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摘要:目的
系统分析肿瘤细胞减灭术（cytoreductive surgery, CRS）加腹腔热灌注化疗（hyperthermic intraperitoneal chemotherapy, HIPEC）治疗胃癌腹膜癌（gastric cancer peritoneal carcinomatosis, GC PC）的应用现状及发展方向。
方法检索CRS+HIPEC治疗GC PC相关临床研究文献，提取生存及安全性相关数据，进行系统分析。
结果GC PC的自然病程不超过5月，CRS+HIPEC可延长GC PC患者总生存期（overall survival, OS）。在前瞻性临床研究中CRS+HIPEC组中位OS为11.0月，在回顾性临床研究中CRS+HIPEC组中位OS为13.3月。CRS+HIPEC治疗GC PC围手术期死亡率低于6.5%，严重不良事件发生率无显著上升。
结论CRS+HIPEC治疗GC PC疗效显著，有望成为部分经选择的GC PC患者的首选治疗。
Abstract:ObjectiveTo evaluate the clinical trials of cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) on gastric cancer peritoneal carcinomatosis (GC PC).
MethodsThe published clinical trials of CRS+HIPEC on GC PC were critically evaluated, with survival and safety as the primary endpoints.
ResultsThe natural course of GC PC was < 5 months. CRS+HIPEC could improve the overall survival (OS). In prospective studies, the median OS was 11.0 months in the CRS+HIPEC group. In retrospective studies, the median OS was 13.3 months in the CRS+HIPEC group. The perioperative mortality was less than 6.5%, and there was no statistically significant increase in serious adverse events directly attributable to CRS+HIPEC.
ConclusionCRS+HIPEC is a promising integrated treatment strategy for GC PC to produce improved treatment efficacy, and should be recommended as the first treatment choice for selected patients with GC PC.
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0 引言
胃癌是世界上癌症相关死亡的三大常见原因之一。目前根治性手术以及放化疗等辅助治疗方案的联合应用，胃癌患者的生存期已显著延长[1]。但是大多数患者最终会对化疗药物产生耐药现象，胃癌患者并不能通过传统的治疗方法受益，因此寻找新的治疗策略是当务之急[2]。有研究发现miR-451可促进消化道肿瘤的发生发展，然而，miR-451是否参与胃癌对5-Fu耐药的调节仍未可知[3]。MRP通过细胞外和细胞内膜运输各种分子，涉及多重耐药性[4]。该蛋白质作为多特异性有机阴离子转运蛋白起作用，是广泛表达于人体各组织中的耐药基因，在调节肿瘤对药物的反应性过程中发挥重要作用。在非小细胞肺癌中，MRP可作为耐药基因影响患者对铂类药物的敏感度[5]。本研究拟通过RT-PCR检测miR-451在胃癌中的表达水平，在细胞水平上分析其对胃癌细胞增殖、迁移能力的影响，并揭示其可能参与的分子调控路径。
1 资料与方法
1.1 资料
293T细胞、胃癌亲本细胞株（BGC-823、SGC-790、MKN-4、MKN-45、MKN-28）及BGC-823耐药细胞株、MKN-4耐药细胞株、MKN-28耐药细胞株均购自ATCC（美国）；DMEM细胞培养基购自SIGMA-ALDRICH公司（德国）；胎牛血清购自Gibco公司（美国）；CCK8试剂盒购自MCE公司（中国）；psPAX2、pMD2G、pLenti-miR-451 or pLenti-control均购自优宝生物（中国）；miRNA-451引物、U6引物、GAPDH引物、MRP引物、NC inhibitor以及miR-451 inhibitor购自广州锐博生物科技有限公司（中国）；RNA提取试剂盒购自TaKaRa公司（日本）；RNA反转录试剂盒（Revert Aid First Strand cDNA Synthesis Kit）以及miRNA Universal SYBR® qPCR Master Mix试剂盒购自南京诺唯赞生物科技有限公司（中国）；一抗GAPDH及辣根过氧化物酶标记的羊抗兔/鼠二抗均购于三鹰生物科技有限公司（中国）；Western blot试剂盒及BCA蛋白浓度测量试剂盒购自碧云天生物技术公司（中国）。
1.2 组织来源
收集西安医学院第一附属医院胃癌患者20例，取癌组织和癌旁组织样本后立即置于-80℃液氮中冷冻待用。
1.3 细胞培养
293T细胞、胃癌细胞系（BGC-823、SGC-790、MKN-4、MKN-45和MKN-28）培养于含10%FBS的DMEM中，BGC-823耐药细胞株、MKN-4耐药细胞株、MKN-28耐药细胞株培养于含1 mg/L的10%FBS的DMEM中，且均在含饱和湿度、5%CO2、37℃的细胞培养箱中培养。
1.4 病毒包装
胰酶消化收集对数期生长的293T细胞，待细胞生长至60%时，按照病毒包装以及转染试剂要求，pLenti-control/pLenti-miR-451:psPAX2: pMD2G=4:3:1混合后，转染入293T细胞，6 h后更换新鲜DMEM培养基，48 h收集细胞上清液用于转染胃癌细胞（MKN-4/MKN-28/BGC-823耐药细胞株）。
1.5 构建稳定过表达细胞系
胰酶消化生长于对数期的胃癌细胞系（MKN-4/MKN-28/BGC-823耐药细胞株），待细胞生长至50%时，按要求转染胃癌细胞，24 h后更换新鲜培养基，持续使用嘌呤霉素（1 mg/L）筛选，2周后，荧光定量PCR检测过表达效率。
1.6 细胞转染
取对数生长期的细胞，以105个/孔密度接种于6孔板中，待细胞融合度达到80%时，采用LipofectamineTM 3000将miR-451 inhibitor转染入胃癌细胞系（MKN-4、MKN-28耐药细胞株），继续培养4 h后，更换含FBS的DMEM培养基继续培养以供后续实验。
1.7 RNA提取及荧光定量
从不同胃癌组织及胃癌细胞系（BGC-823、SGC-790、MKN-4、MKN-45、MKN-28）中提取RNA用于测定胞内miR-451的相对表达量。按照RNA提取试剂盒要求提取RNA，按照反转录试剂盒要求将其反转录为CDNA，合成的CDNA按照miRNA Universal SYBR®qPCR Master Mix试剂盒要求进行PCR扩增，以U6为内参检测miR-451的表达，以GAPDH为内参检测MRP的表达。U6正向引物序列：5’-GCTTGCTTCAGCAGCACATA-3’，反向引物：5’-AAAAACATGGAACTCTTCACG-3’；miR-45正向引物：5’-CCGAAACCGTTACCATTAC-3’，反向引物：5’-GTGCAGGGTCCGAGGT-3’；GADPH正向引物：5’-GGCATGGACTGTGGTCATGAG-3’，反向引物：5’-TGCACCACCAACTGTTAGC-3’；MRP正向引物：5’-CCCGCTCTGGGACTGGAA-3’，反向引物：5’-ACTTGTTCCGACGTGTCCTC-3’。以上实验均重复三次。
1.8 Western blot检测MRP的表达
取处理好的细胞，加入RIPA裂解液后冰浴30 min使细胞充分裂解，120 000 r/min 4℃，离心10 min，取上清液，蛋白定量，SDS-PAGE电泳2 h，NC膜转膜2.5 h，室温用含5%脱脂奶粉的TBST封闭1 h，一抗MRP以1:2 000配制，β-actin以1:5 000配制，室温孵育4 h，TBST溶液洗3次，每次10 min，二抗以1:5 000稀释配制，室温孵育1 h，TBST溶液洗3次，每次10 min，曝光显影。
1.9 荧光素酶实验
将稳定过表达miR-451的BGC-823、MKN-4耐药细胞株以及对照细胞株接种于24孔板（1.0×105个/孔）。24 h后，将pGL3-MRP-3’野生型以及突变型质粒转染稳定过表达的上述细胞，海参荧光素酶作为内参，24 h后检测荧光素酶活性差异。
1.10 CCK8检测细胞活力
取稳定过表达miR-451的BGC-823、MKN-4耐药细胞株，接种于96孔板（2×103个/孔）中，每组设4个平行复孔。分别加入0、2、4、6、8、10 g/ml 5-Fu，48 h后避光加入20 μl CCK-8溶液，常规孵育2.5 h后，多功能酶标仪检测450 nm波长处的吸光度（A）值，计算细胞增殖能力。
1.11 统计学方法
应用SPSS16.0软件进行统计分析，相关性分析符合Pearson相关性分析方法，计量数据用均数±标准差（x±s）表示，组间比较采用t检验，每组实验至少重复3次，P < 0.05为差异有统计学意义。
2 结果
2.1 miR-451在不同胃癌组织及胃癌细胞系中的表达
RT-PCR检测结果显示耐药胃癌组织中miR-451表达量明显低于非耐药胃癌组织（P=0.00043）。胃癌细胞株MKN-4 miR-451相对表达量为9.26±1.02，MKN-28细胞系中miR-451相对表达量为63.42±6.84，见图 1。
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图 1 RT-PCR检测不同胃癌组织及细胞系中miR-451相对表达量Figure 1 Relative expressions of miR-451 in different gastric cancer tissues and cell lines detected by RT-PCR2.2 miR-451过表达抑制胃癌细胞增殖且降低胃癌细胞对5-Fu的耐药性
构建miR-451稳定过表达MKN-4耐药细胞株，结果显示miR-451显著过表达。miR-451 inhibitor转染MKN-28耐药细胞株，结果显示miR-451表达明显受到抑制，见图 2A。在不同5-Fu浓度刺激下，过表达miR-451可明显降低耐药细胞的增殖能力，抑制miR-451表达可促进耐药细胞系的增殖能力，见图 2B。
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图 2 RT-PCR检测miR-451的表达(A)及CCK8检测不同5-Fu浓度下胃癌细胞的增殖能力(B)Figure 2 miR-451 expression and proliferation ability of gastric cancer cells treated with different concentrations of 5-Fu detected by RT-PCR(A) and CCK8(B)2.3 MiR-451对MRP表达的调节作用
miRBase、TargetScan、miRanda、miRDB生物数据库分析结果显示MRP为miR-451的靶基因，见图 3A。随之，构建MRP野生型以及突变型荧光报告质粒，见图 3B。荧光素酶报告实验证明，在转染野生型的双荧光报告质粒后，miR-451过表达使荧光素酶相对活性明显降低（P < 0.01），而突变型则无限制变化，见图 3C~D。以上结果证明miR-451靶向MRP的3’UTR。
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图 3 miR-451的靶基因分析Figure 3 Analysis of miR-451 target geneA: Bioinformatics analysis results showed that MRP was the target gene of miR-451; B: We constructed 3'UTR wild-and mutant-type dual fluorescein reporter plasmids of MRP; C, D: miR-451 regulated the fluorescence activity of wild-type and mutant MRP reporter plasmids in BGC-823 and MKN-4 cells2.4 miR-451调控MRP的表达
miR-451过表达可明显抑制MRP转录（P=0.00075），见图 4A。20例胃癌组织中miR-451以及MRP mRNA水平显著负相关，见图 4B。Western blot检测结果显示过表达miR-451可显著降低MRP蛋白水平（P=0.000045），而miR-451 inhibitor抑制miR-451表达后，其蛋白水平出现明显上调（P=0.00029），见图 4C。
2.5 过表达MRP可促进耐药细胞系对5-Fu的耐药性
在稳定过表达miR-451的耐药细胞系BGC-283以及MKN-4中过表达MRP，Western blot实验证明了MRP的过表达效率（P=0.000062）。相对单一过表达miR-451的胃癌细胞系，miR-451可明显增加胃癌耐药细胞系BGC-283以及MKN-4对5-Fu的敏感度，其细胞增殖能力明显低于对照组；而CCK8检测结果显示，相对于单一过表达miR-451，过表达miR-451和MRP可明显增加细胞的增殖能力（P=0.00032），见图 5。说明MRP可增加胃癌细胞对5-Fu的耐受能力。
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图 5 CCK8检测MRP对胃癌细胞增殖能力的影响Figure 5 Effect of MRP on proliferation of gastric cancer cells detected by CCK8 assay3 讨论
药物抵抗是目前胃肠道肿瘤治疗的一大难题，现有的胃肠道肿瘤治疗方案难以进一步提高患者的生存期，开发新的药物靶点是肿瘤治疗的当务之急[6]。MicroRNA作为非编码RNA参与肿瘤细胞的增殖、分化以及凋亡，有文献证明了microRNA作为治疗靶点用于肿瘤等疾病的可行性[7]。Tsuchiya等[8]发现miR-451有助于上皮细胞基底外侧极性的形成。Ribeiro-dos-Santos等[9]通过高通量测序建立了人胃组织miRNA表达谱，结果发现miR-31、miR-9b、miR-148a以及miR-451在胃癌组织中高度表达，说明miR-451可作为药物治疗的靶点用于胃癌的辅助治疗。在非小细胞肺癌中，miR-451可通过抑制AKT信号通路的激活增加肺癌对顺铂的敏感度[10]。Liu等[11]发现过表达miR-451能够降低肺癌细胞对伊马替尼的耐药作用，提高TKI的疗效。此外，在乳腺癌中，他莫昔芬也可诱导miR-451的上调，降低肿瘤细胞的抵抗效果[12]。本研究发现，miR-451参与胃癌细胞对5-Fu的耐药作用。RT-PCR检测结果显示miR-451在非耐药胃癌中表达量高于耐药胃癌组织，CCK8实验显示miR-451参与调节胃癌细胞对5-Fu的耐药作用，证明miR-451可明显降低细胞对5-Fu的耐药性，并通过生物信息学分析的方法证明了耐药基因MRP为miR-451的靶基因，荧光素酶报告实验显示上调miR-451可明显抑制野生型MRP的荧光强度，RT-PCR以及Western blot实验验证了上调miR-451可抑制MRP的表达，而抑制miR-451可促进MRP的表达，表明miR-451通过与MRP的3'UTR结合直接调节其表达。MRP作为调节肿瘤细胞对各种药物的耐药作用已被证实，O'Meara等[13]发现MRP可能参与HIV耐药，MRP可通过影响抗HIV药物转运至转染的细胞中抑制药物对HIV的杀伤。Boumendjel等[14]发现MRP也可影响抗结核杆菌药物的转运，增加结核杆菌的耐药现象。以上说明MRP在耐药方面发挥广泛的作用。
本研究阐述了miR-451异常表达介导了胃癌细胞系对5-Fu的耐药作用，并通过生物信息学相关分析，证明了miR-451通过靶基因MRP影响胃癌细胞对5-Fu的耐药作用，为目前寻找胃癌耐药方面的治疗提供了新的思路以及依据。
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表 3 CRS+HIPEC相关并发症发生率、死亡率及严重不良事件
Table 3 Mortality, morbidity and serious adverse events (SAEs) of CRS+HIPEC
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